U.S. patent number 5,651,987 [Application Number 08/113,485] was granted by the patent office on 1997-07-29 for ulcer prevention and treatment composition.
This patent grant is currently assigned to Fuisz Technologies Ltd.. Invention is credited to Richard C. Fuisz.
United States Patent |
5,651,987 |
Fuisz |
July 29, 1997 |
**Please see images for:
( Certificate of Correction ) ** |
Ulcer prevention and treatment composition
Abstract
Anti-ulcer compositions are disclosed having therapeutic agents
dispersed in a soluble matrix formed by melt spinning the
therapeutic agent with a carrier and hydrogel. Methods of treating
ulcer-bearing tissue and preparing the matrix are also disclosed.
One embodiment includes use of gastric irritating bio-affecting
agents in which case the composition is preventative as well as
therapeutic.
Inventors: |
Fuisz; Richard C. (Great Falls,
VA) |
Assignee: |
Fuisz Technologies Ltd.
(Chantilly, VA)
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Family
ID: |
25199224 |
Appl.
No.: |
08/113,485 |
Filed: |
August 27, 1993 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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808599 |
Dec 17, 1991 |
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Current U.S.
Class: |
424/488; 424/500;
514/925; 424/485; 424/499; 424/487; 424/501 |
Current CPC
Class: |
A61K
9/1652 (20130101); A61K 31/426 (20130101); A61K
31/415 (20130101); A61K 31/7135 (20130101); A61K
31/616 (20130101); A61K 31/192 (20130101); A61K
31/70 (20130101); A61K 31/341 (20130101); A61K
31/4439 (20130101); A61K 9/70 (20130101); A61K
31/4164 (20130101); A61P 1/04 (20180101); A61K
31/70 (20130101); A61K 31/19 (20130101); A61K
31/70 (20130101); A61K 31/60 (20130101); A61K
31/70 (20130101); A61K 2300/00 (20130101); Y10S
514/925 (20130101) |
Current International
Class: |
A61K
31/4427 (20060101); A61K 31/4439 (20060101); A61K
31/70 (20060101); A61K 9/16 (20060101); A61K
9/70 (20060101); A61K 31/415 (20060101); A61K
31/4164 (20060101); A61K 31/341 (20060101); A61K
31/426 (20060101); A61K 009/10 (); A61K
009/14 () |
Field of
Search: |
;424/484,485,487,488,499,500,507 ;514/925 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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609135 |
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Apr 1988 |
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AU |
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609137 |
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Apr 1988 |
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AU |
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900605 |
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Nov 1977 |
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BE |
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1303511 |
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Apr 1988 |
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CA |
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86052 |
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Apr 1988 |
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IL |
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86053 |
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Apr 1988 |
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IL |
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88/2771 |
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Apr 1988 |
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ZA |
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88/2770 |
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Apr 1988 |
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ZA |
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89/9318 |
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Dec 1989 |
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ZA |
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90/2139 |
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Mar 1990 |
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ZA |
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90/8406 |
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Aug 1991 |
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ZA |
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Primary Examiner: Webman; Edward J.
Attorney, Agent or Firm: Hoffmann & Baron
Parent Case Text
This is a Continuation-in-Part application of PCT/US 92/10978 filed
Dec. 16, 1992, which in turn is a Continuation-in-Part of U.S.
application Ser. No. 808,599 which was filed on Dec. 17, 1991
abandoned.
Claims
What is claimed is:
1. An anti-ulcer composition having rapid delivery and enhanced
adherence to ulcer-bearing tissue comprising:
a solid matrix having suspended therein an anti-ulcer medicament,
said matrix formed by flash-flow melt-spinning a mixture of
i) a melt-spinnable carrier material present in an amount
sufficient to form a flash-flow melt-spun matrix when said
anti-ulcer medicament is dispersed therein;
ii) an anti-ulcer medicament present in an amount sufficient to
achieve a therapeutic effect; and
iii) a hydrogel in addition to said carrier material, said hydrogel
being selected from the group consisting of gums, cellulose,
pectins, gelatin, polycarbophil, alginate and mixtures thereof to
provide mucosal adherence.
2. The composition of claim 1, wherein said anti-ulcer medicament
is sucralfate.
3. The composition of claim 1, wherein said anti-ulcer medicament
is selected from the group consisting of cimetidine, ranitidine,
nizatidine, famotidine, omeprazole and mixtures thereof.
4. The composition of claim 1, wherein said medicament is present
in an amount of from about 0.1 to about 50% by weight of said
matrix.
5. The composition of claim 4, wherein said medicament is present
in an amount of from about 0.1 to about 20% by weight of said
matrix.
6. The composition of claim 1, wherein said carrier material is
selected from the group consisting of maltodextrins, corn syrup
solids, polydextrose, maltooligosaccharides and mixtures
thereof.
7. The composition of claim 6, wherein said hydrogel is selected
from the group consisting of xanthan gum, guar gum, carrageenan
gum, gum tragacanth, sodium alginate, gum karaya, locust bean gum,
gum acacia and mixtures thereof.
8. The composition of claim 7 wherein said hydrogel is present in
an amount of from about 0.2 to about 4% by weight of said
matrix.
9. The composition of claim 8 wherein said hydrogel is present in
an amount of from about 0.8 to about 2.5% by weight of said
matrix.
10. The composition of claim 1 wherein said hydrogel is cellulose
or a cellulose derivative.
11. The composition of claim 10, wherein said hydrogel
hydroxypropylmethyl cellulose is HPMC.
12. The composition of claim 11, wherein said anti-ulcer medicament
is sulcralfate.
13. The composition of claim 10, wherein said hydrogel is xanthan
gum.
14. The composition of claim 1 which further comprises a
gastric-irritating bio-affecting agent.
15. The composition of claim 14, wherein said bio-affecting agent
is a non-steroidal anti-inflammatory (NSAI) agent.
16. The composition of claim 15 wherein said non-steroidal
anti-inflammatory (NSAI) is selected from the groups consisting of
salicylate NSAI agents, acetic acid NSAI agents, oxicam NSAI
agents, oxidole NSAI agents and mixtures thereof.
17. The composition of claim 14 wherein said bio-affecting agent is
a steroid.
18. The composition of claim 17 wherein said steroid is selected
from the group consisting of andrenocorticoids and
corticotropins.
19. The composition of claim 1 wherein an antacid is included in
said matrix by subjecting said antacid to flash-flow along with
said medicament and said mixture.
20. The composition of claim 19 which further comprises a
non-steroidal anti-inflammatory (NSAI) agent subjected to
flash-flow with said antacid and said medicament and said
mixture.
21. An anti-ulcer medication comprising:
a) an anti-ulcer medicament dispersed in a first matrix formed by
subjecting to flash-flow condition a first feedstock comprising
said medicament and a mixture comprising a saccharide carrier
material and a hydrogel selected from the group consisting of gums,
celluloses, pectins, gelatin, polycarbophil, alginate and mixtures
thereof to provide mucosal adherence;
b) an antacid agent dispersed in a second matrix formed by
subjecting flash-flow conditions a second feedstock comprising said
antacid and a carrier material comprising a saccharide.
22. The medication of claim 21 wherein said first feedstock further
comprises a non-steroidal anti-inflammatory (NSAI) agent.
23. The medication of claim 21 wherein said second feedstock
further comprises a non-steroidal anti-inflammatory (SAI)
agent.
24. A pharmaceutical composition having rapid delivery and enhanced
adherence to mucosal tissue comprising:
a solid matrix having suspended therein a medicament, said matrix
formed by flash-flow melt-spinning a mixture of
i) a melt-spinnable carrier comprising a saccharide present in an
amount sufficient to form a flash-flow melt-spun matrix when said
medicament is dispersed therein;
ii) a medicament present in an amount sufficient to achieve a
therapeutic effect; and
iii) a hydrogel in addition to said carrier, said hydrogel being
selected from the group consisting of gums, celluloses, pectins,
gelatin, polycarbophil, alginate and mixtures thereof to provide
mucosal adherence properties.
25. The pharmaceutical composition of claim 24 wherein the
medicament is a drug which acts systematically.
26. The pharmaceutical composition of claim 25 wherein the drug is
selected from the group consisting of anti-infectives and
anti-lipid agents.
27. The pharmecutical composition of claim 24 wherein the carrier
is selected from the group consisting of maltodextrins, corn syrup
solids, polydextroses, maltooligo-saccharides and mixtures
thereof.
28. The pharmecutical composition of claim 24 wherein said hydrogel
is selected from the group consisting of xanthan gum, guar gum,
carrageenan gum, gum tragacanth, sodium alginate, gum karaya, locus
bean gum, gum acacia and mixtures thereof.
29. The composition of claim 28 wherein said hydrogel is present in
an amount of from about 0.2 to about 4% by weight of said
matrix.
30. The composition of claim 24, wherein said solid matrix further
comprises an oleaginous substance in an amount sufficient to
provide even distribution of said medicament.
31. The composition of claim 30 wherein said oleaginous substance
is selected from the group consisting of corn oil, sunflower oil,
olive oil, vegetable oils and mixtures thereof.
32. The pharmaceutical composition of claim 24 wherein said
hydrogel is cellulose or a cellulose derivative.
33. The composition of claim 32 wherein said cellulose is
hydroxypropylmethyl cellulose HPMC.
34. The pharmacutical composition of claim 32 wherein the cellulose
is selected from the group consisting of
hydroxypropylmethylcellulose, hydroxyethylcellulose,
methylcellulose, carboxymethylcellulose, hydroxymethylcellulose and
mixtures thereof.
35. The pharmacutical composition of claim 24 wherein said hydrogel
is xanthan gum.
Description
BACKGROUND OF THE INVENTION
The present invention relates to ulcer treatments. In particular,
the present invention relates to the use of dosage forms containing
anti-ulcer agents dispersed in a soluble matrix.
Sucralfate is a therapeutic compound useful for treatment of
various gastrointestinal disorders. Sucralfate accelerates the
healing of gastric and duodenal ulcers and also finds use as a
symptomatic treatment for disturbances such as dyspepsia and
reflux.
Sucralfate displays its action in the acid medium of the digestive
tract where it lines ulcerated mucous membranes of the stomach and
duodenum with a protective coating. The preferential binding
affinity of sucralfate for ulcerated areas of mucous membrane
results in increased protection and accelerated healing of ulcers
as well as regeneration of the mucous membrane.
Although sucralfate is usually taken orally in the form of tablets,
other dosage forms are known. For example, U.S. Pat. No. 4,885,281
discloses an aqueous suspension containing sucralfate, xanthum gum
and a "peptiser". Peptisers such as salts of inorganic or organic
acids are added to ensure that the xanthan gum does not separate
out of the suspension by gel formation.
Belgium Patent No. 900,605 discloses a composition of sucralfate
and a nonsteroidal anti-inflammatory product. The compositions were
prepared for administering to mammalian test specimens by
suspending the active substances in an aqueous medium containing
0.5% sodium CMC (carboxymethylcellulose).
The preparation of melt-spun medicament-containing products is
known. For example, commonly-assigned U.S. Pat. No. 4,855,326,
which is incorporated by reference herein, discloses combining a
medicament with a melt-spinnable carrier agent, preferably a
mixture of sucrose and lactose, and then melt-spinning the mixture
to form a spun product.
Similarly, commonly-assigned U.S. Pat. No. 4,997,856, also
incorporated by reference herein, discloses melt spun, compacted
dispersible systems containing a medicament, saccharide and an
oleaginous substance such as a food oil.
In keeping with the foregoing, improvements are continuously being
sought using high shear and/or heat processing to enhance the
delivery of medicaments. In the case of anti-ulcer medicaments such
as sucralfate, an investigation is being conducted to improve the
protective and therapeutic action of the medicament on ulcerated
areas of mucous membranes.
It is an object of the present invention to provide an improved
method of treatment using medicaments spun in a matrix carrier.
It is a further object of the present invention to provide improved
methods and compositions for preventing and treating ulcerated
mucosa.
Other and further objects will become apparent to the artisan in
view of the present disclosure, and the scope of the present
application is not to be limited by the objects set forth
above.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a photograph of two containers of sucralfate
compositions, using HPMC as a thickener, which were reconstituted
with water and shaken to obtain a suspension. The container marked
"Processed-Shaken" is a flash flow formed matrix made in accordance
with the present invention. The container marked
"Unprocessed-Shaken" shows a suspension of the identical
formulation which has not been flash flow processed, but mixed as a
simple powdered mixture. The wettability, uniformity and
completeness of the resultant dispersion is evident from the
photograph.
FIG. 2 is a photograph of two containers of sulcrafate
compositions, using HPMC as a hydrogel, which were reconstituted
with water without shaking. The "Processed-Unshaken" and
"Unprocessed-Unshaken" markings have the meanings as in FIG. 1. The
failure of the unprocessed simple mixture to fully wet and fall
into suspension is evident.
FIG. 3 is a photograph of two containers of sucralfate compositions
using xanthan gum as a hydrogel suspension aid and which were
constituted with water and shaken to obtain a suspension. The
"Processed-Shaken" and "Unprocessed-Shaken" markings have the
meanings as in FIG. 1. The wettability, uniformity and completeness
of the resultant dispersion formed from the inventive (Processed)
matrix compositions. The failure of the unprocessed mixture to
fully wet and form a uniform suspension is evident.
FIG. 4 is a photograph of two containers of sucralfate compositions
using xanthan gum as a hydrogel suspension aid and which were
reconstituted with water without shaking. The failure of the
unprocessed mixture, as compared to the inventive flash flow
processed composition; to fully wet and fall into suspension is
evident.
SUMMARY OF THE INVENTION
The present invention includes anti-ulcer compositions formed by
having a medicament dispersed in a soluble matrix. The soluble
matrix is formed by subjecting the feedstock to physical and/or
chemical changes associated with flash flow processing, such as by
melt-spinning the medicament with a mixture of a carrier material
and a hydrogel. The anti-ulcer compositions can either be placed
directly on the ulcer-bearing tissue/mucosa or may be dispersed in
a liquid before contacting the affected tissue.
The medicament included in the composition of the present invention
is preferably sucralfate. Alternatively, H.sub.2 -blocking agents
such as cimetidine and the like or omeprazole may also be
included.
The carrier materials included in the mixture are a
saccharide-based and preferably materials such as maltodextrin,
maltooligosaccharides or polydextrose. The hydrogel is selected
from materials such as xanthan gum, guar gum and carrageenan. In a
preferred embodiment, the melt spinning mixture also includes an
oleaginous substance such as a vegetable oil. A method of preparing
such anti-ulcer compositions is also disclosed.
The composition of the present invention can also include an
analgesic and non-steroidal anti-inflammatory (NSAI) agent. The
non-steroidal anti-inflammatory agent may be selected from the
various classes of such compounds, e.g., salicylates, acetic acids,
propionic acids, fenamates, oxicams, and oxidoles. A processing
aid, such as glycerin, can be used in manufacture of the
composition.
The composition of the present invention can also include steroids
or other gastric irritating drugs. The steroids may be
andrenocorticoids such as betamethasone, cortisone, dexamethasone,
hydrocortisone, methylprednisolone, paramethasone, prednisolone,
prednisone, triamcinolone or corticotropins and the like. Examples
of steroids include, but are not limited to, medicaments set forth
by trade name as follows: Aristocort - Lederle; Hydrocortone -
Merck Sharp & Dohme; Kenalog (in Orabase) - Squibb; Cortone -
Merck Sharp & Dohme; Decadron - Merck Sharp & Dohme; and
Medrol - Upjohn.
In yet another embodiment an antacid can be included in the
composition. The antacid can be incorporated in the feedstock
before being processed under flash-flow condition, or,
alternatively, it can be separately processed under flash-flow
conditions and combined in a delivery system. For example, the
antacid can be processed separately to form flakes which can then
be combined with flakes bearing an anti-ulcer medicament and
optionally an analgesic, by tabletting the flakes together in a
single tablet.
The present invention also includes a method of treating
ulcer-bearing tissue. The method includes contacting the affected
tissue with an anti-ulcer medicament dispersed in a soluble matrix
as set forth above. Preferably, the medicament-containing matrix
has been dispersed in a liquid such as water before contacting the
ulcer-bearing tissue.
In a further embodiment, the present invention includes a
pharmaceutical composition having rapid delivery and enhanced
adherence to mucosal tissue. The pharmaceutical composition
comprises a solid matrix having suspended therein a medicament, the
matrix being formed by flash-flow melt-spinning a mixture of a
melt-spinnable carrier material present in an amount sufficient to
form a flash-flow melt-spun matrix when the medicament is dispersed
therein; a medicament present in an amount sufficient to achieve a
therapeutic effect; and a hydrogel which demonstrates mucosal
adherence properties and which is present in an amount sufficient
to assist in suspending the medicament in the matrix. The
medicament can be any drug which can be flash-flow processed. For
example, it may be selected from the group consisting of
anti-infectives and anti-lipid agents. The carrier can be selected
from the group consisting of maltodextrins, corn syrup solids,
polydextroses, maltooligo-saccharides and mixtures thereof. The
hydrogel can be selected from water-soluble polymers, hydrocolloids
or hydrophilic polymers which are useful as mucosal adherence
materials, such as xanthan gum, guar gum, carrageenan gum, gum
tragacanth, sodium alginate, gum karaya, locus bean gum, gum acasia
and mixtures thereof. The hydrogel is present in an amount from
about 0.2 to about 5.2% by weight of the matrix. The solid matrix
may further contain an oleaginous substance, which, for example,
may be selected from the group consisting of corn oil, sunflower
oil, olive oil, vegetable oils and mixtures thereof. Further, the
hydrogel may be a cellulose. A non-limiting list of cellulose
hydrogels useful in the present invention include those selected
from the group consisting of hydroxypropylmethylcellulose,
hydroxyethylcellulose, methylcellulose, carboxymethylcellulose,
hydroxymethylcellulose and mixtures thereof.
As a result of the present invention, anti-ulcer compositions are
provided which present therapeutic agents in a rapidly soluble
form. In addition, since the therapeutic agents are melt spun with
a hydrogel in addition to a soluble carrier, the composition
demonstrates mucosal adherence properties and enhanced mouthfeel
due to the thickening effect of the hydrogel. These added features
provide an enhanced therapeutic effect as well by rapidly placing
the anti-ulcer medicament in contact with the affected tissue and
affixing it there for a period of time. The hydrogel also acts to
assist in suspending the medicament during melt spinning within the
spun matrix. The hydrogel is present in an amount sufficient to
assist in suspending the medicament in the matrix.
Moreover, when the active agents set forth above are prepared in
accordance with the present invention, the product has a markedly
enhanced tabletting capability. This product is ideal for preparing
tabletted delivery systems such as pills, etc.
Yet another advantage is that the compositions of the present
invention provide good coating action for internal tissue surfaces
of the body by virtue of their substantially uniform adherence to
mucosal tissue.
For a better understanding of the present invention, reference is
made to the following description, and its scope will be pointed
out in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The anti-ulcer compositions of the present invention are formed by
melt spinning medicaments with a mixture of a carrier material and
hydrogel so that the medicament is suspended in a soluble
matrix.
When a non-steroidal anti-inflammatory agent is included,
sucralfate and the NSAI agents are admixed prior to processing. In
a preferred embodiment, the carrier material is also mixed with the
active ingredients prior to processing. A processing aid can be
used to provide bulk for thorough mixing. Glycerin is useful as a
processing aid.
The active ingredients are subjected to flash-flow processing.
Flash-flow processing can be accomplished several ways. Flash heat
and flash shear are two such processes which can be used. In the
flash heat process, the feedstock material is heated sufficiently
to create an internal flow condition which permits part of the
feedstock to move at a subparticle level with respect to the rest
of the mass and exit openings provided in the perimeter of a
spinning head. The centrifugal force created in the spinning head
flings the flowing feedstock material outwardly from the head so
that it reforms with a changed structure. The force required to
separate and discharge a flowable feedstock is centrifugal force
which results from the spinning head. The flash heat process is one
process for producing the product of this invention.
In the flash shear process, a shearform matrix is formed by raising
the temperature of the feedstock material which includes a
nonsolublized-carrier to a point where the carrier such as a
saccharide-based material undergoes internal flow upon application
of a fluid shear force. The feedstock is advanced and ejected while
in internal flow condition, and subjected to disruptive fluid shear
forces to form multiple parts or masses which have morphology
different from that of the original feedstock.
The multiple masses are cooled substantially immediately after
contact with the fluid shear force and are permitted to continue in
a free-flow condition until solidified.
In the flash heat process, a spinning process is used herein,
wherein the medicament is combined with a carrier and is spun with
"cotton candy" fabricating type equipment. The floss spinning
machine used herein can be any cotton candy type machine, such as
the Econofloss Model 3017 manufactured by Gold Metal Products
Company of Cincinnati, Ohio. It will be appreciated by those
skilled in the art from the present description that any apparatus
or physical process which provides similar forces and temperature
gradient conditions can also be used. For simplicity in disclosing
and describing this invention, the term "melt-spinning" will be
understood to mean a process which includes a combination of
temperature, shear, flow, flow rate, mechanical forces and thermal
gradients of the type utilized in a cotton candy type machine.
In melt-spinning, the stock material, historically sucrose, is
melted and forced through spinerettes. Conventional equipment
includes a rotating spinning head surrounded by a bowl into which
the fibers are spun. Typically, the temperature of the grid in the
spinning machine required for spinning sucrose is from about
180.degree. F. to about 266.degree. F. at operating speeds of about
3800 RPM. Other saccharides such as maltodextrins and polydextrose,
however, can be spun at temperatures as much as 30 to 40% lower and
thus permit many heat-sensitive materials to safely undergo melt
spinning. It has also been discovered that the extremely short
amount of time the medicaments, saccharides and hydrogels are
exposed to the melt spinning temperature and shear allows the
inventive matrix to be formed without harm.
The flash shear process can be carried out in an apparatus which
has means for increasing the temperature of a non-solubilized
feedstock and means for simultaneously advancing it for ejection. A
multiple heating zone twin screw extruder can be used for
increasing the temperature and advancing feedstock. The second
element of the apparatus is a means for ejecting the feedstock in a
condition for shearing it to provide the product. The means for
ejecting is in fluid communication with the means for increasing
the temperature and is arranged at the point to receive the
feedstock while it is in the internal flow conditions. The means
for ejecting the feedstock is preferably a nozzle which provides
high pressure ejection of the feedstock material. For a description
of various apparati which can be used to produce the inventive
delivery systems, see copending U.S. Ser. No. (07/965,804), filed
Oct. 23, 1992 entitled "Process for Making Shearform Matrix", which
is herein incorporated by reference.
Various anti-ulcer agents, such as H.sub.2 -blocking agents may be
included in the anti-ulcer composition of the present invention. A
non-limiting list of such agents include cimetidine, ranitidine,
nizatidine and famotidine. Alternatively, anti-ulcer agents such as
omeprazole may be selected. In a preferred embodiment, however, the
anti-ulcer agent is sucralfate. Mixtures of the above-identified
medicaments are also contemplated.
The anti-ulcer agent will be present in amounts up to 50% by weight
and preferably from 0.1 to about 20% by weight of the matrix. Most
preferably, however, the medicament is present in amounts of from
about 0.5 to about 15% by weight of the matrix. The amount of
medicament in the matrix is that amount sufficient to achieve the
desired therapeutic result. The optimum dosing of the anti-ulcer
medicaments is left with the skill of the artisan.
The anti-ulcer medicament is melt spun with a mixture of a carrier
material and hydrogel. The carrier material is preferably a
saccharide-based material. A non-limiting list of suitable
saccharides include sucrose, maltose, fructose, glucose and
lactose. Alternatively, carrier materials can be selected from
maltodextrins, polydextrose, corn syrup solids,
maltooligosaccharides and mixtures thereof.
The hydrogels included in the melt-spinning mixture are selected
from materials such as xanthan gum, guar gum, carrageenan gum, gum
tragacanth, similar materials, and mixtures thereof. The hydrogel
will be present in an amount of from about 0.2% to about 4% by
weight of the matrix, with amounts of from about 0.8 to about 2.5%
being preferred.
Hydrogels, which may also be referred to as water-soluble polymers,
hydrocolloids or hydrophilic polymers, demonstrate the property of
being able to adhere to mucous membranes. Materials such as
pectins, gelatin, celluloses and polycarbophil are also of use. By
including such mucous-adhering materials in the matrix, the
anti-ulcer medicament can be maintained in contact with the
affected area, that is, ulcer-bearing tissue. For example, upon
contact with ulcer-bearing mucosal tissue, the saccharide portion
of the matrix quickly dissolves, leaving the medicament and
hydrogel adhering to the affected area. Even when the matrix is
dispersed in a liquid before administration, adherence of the
medicament to mucosal areas is observable. Thus, the therapeutic
properties of the medicament can be directed and affixed to the
particular area needed.
Nonlimiting examples of cellulose hydrogels which are useful in the
present invention include hydroxypropylmethylcellulose(HPMC),
hydroxyethylcellulose(HEC), methylcellulose,
carboxymethylcellulose(CMC), hydroxymethylcellulose(HMC) and
mixtures thereof. As previously mentioned, the matrices of the
present invention can be used to rapidly form suspensions. The
ability to form suspensions is greatly enhanced over conventional
simple mixtures and processing techniques. This enhancement is
related to the unique morphology of the solid formed matrix which
provides greater surface area contact between the soluble carrier
material and the reconstituting medium, e.g. water.
Unprocessed mixtures, i.e., mixtures of medicament, carrier and
hydrogel which have not been melt spun produce only partially
wettable suspensions, which are therefore less uniform, less
complete and consequently less effective at deliverying the
drug.
A variety of medicaments in addition may be added to sucralfate to
the compositions of the present invention. For the purpose of this
invention, medicaments shall include drugs and other bioeffecting
agents. Other useful drugs include, without limitation, those
disclosed in U.S. Pat. No. 4,855,326 to Fuisz, which is
incorporated herein by reference. Examples of classifications of
these medicaments include acne preparations, analgesics,
antipyretics, antacids, antiflatulents, anthelmintics,
antianginals, antianxietals, antiarrythmics, antiarthritics,
anticoagulants, antithrombotics, anticonvulsants, antiParkinson
agents, antidepressants, antidiarrheals, antifungals,
antitrichomonals, antivitals, antigout agents, antihistamines,
antipruritics, antihypertensives, antiinfectives, antimigraines,
antinauseants (antiemedics), antineoplastics, antiulcer agents,
antireflux agents, antispasmodics, bronchodilaters, antiasthmatics,
cardiac agents, contraceptives, hormonals, steroids, cough/cold
remedies, diuretics, hypoglycemics, hypolipidemics, laxatives,
tranquilizers, muscle relaxants, opthalmic preparations, mineral
supplements, sedatives, hypnotics, vitamins and mixtures thereof.
Preparations using these medicaments for their intended purposes
can take a variety of forms including tablets, lozenges, granules
or powders, capsules, elixirs, creams, solutions, syrups as well as
other forms or delivery vehicles.
The suspensions formed by the present invention can be tested using
a shake test, whereby the solid matrices are reconstituted with
liquid medium, i.e. water, shaken and the resultant dispersion
observed for uniformity, completeness and stability. As would be
expected, wettability of the matrix is extremely important in
creating a proper dispersion. Wettability is the ability of a solid
to make its surface available to the reconstituting liquid, with
little or no clumping or caking, and rapidly dissolve or disperse.
Uniformity of suspension refers to the ability of the composition
to completely and uniformly disperse in the reconsituting medium.
Stability refers to the ability of the particles to remain in
suspension for extended periods of time, as well as the ability to
be resuspended by a shaking motion, without irreversibly clumping
or agglomerating during the settling out process.
In the preferred embodiment of the present invention, whereby the
carrier, medicament and hydrogel are melt-spun together to form the
resultant matrices, wettability is particularly enhanced and
dispersions made from these matrices have excellent speed of
formation, uniformity and completeness, as well as stability. The
medicaments are present in amounts useful for the intended purpose,
which can be determined by routine experimentation by those skilled
in the art.
In a further embodiment of the present invention, the mixture of
the carrier material and hydrogel can also include an oleaginous
substance which functions to assure that as the matrix is formed
during melt spinning, the active ingredient is substantially evenly
distributed in the carrier. In this regard, oleaginous substances
such as polyvinylpyrrolidone (PVP) or vegetable oils such as corn
oil, sunflower oil, olive oil and mixtures thereof may be present
in amounts of from about 2 to about 20% by weight of the matrix,
with amounts of from about 5 to about 15% being preferred.
The medicament, hydrogel, and carrier material may be combined
prior to or during melt spinning. For example, the mixture
containing the carrier and hydrogel are first combined into a
uniform mixture before adding the medicament and any optionally
present materials such as flavors, sweeteners or oleaginous
materials.
In one embodiment, the composition can also include a non-steroidal
anti-inflammatory (NSAI) agent selected from the various classes of
such compounds. Such classes include, for example, salicylates such
as acetylsalicylic acid and diflunisal; acetic acids such as
indomethacin, sulindac, tolmetin, diclofenac, and etodolac;
propionic acids such as flurbiprofen, indoprofen, naproxen, and
ketoprofen; fenamates such as meclofenamate; oxicams such as
piroxicam; and oxindoles such as tenidap.
When the composition incudes an NSAI agent, the actives are
preferably mixed prior to flash-flow processing. The actives can be
mixed with a processing aid which can be glycerin, for example.
The anti-ulcer composition may also optionally include a flavorant.
Flavorants include flavors, sweeteners and combinations thereof.
The flavors may be natural, artificial or mixtures thereof while
the sweeteners may be natural, artificial or high intensity
sweeteners or mixtures thereof. Such flavorant materials can be
melt spun with the medicament and carrier/hydrogel mixture so that
the flavorant is also dispersed within the spun matrix. The amount
of flavorant included in the matrix will be a matter of preference
for the artisan. It is anticipated that the flavorant will be
present in amounts of from about 0.01 to about 3% by weight of the
matrix. In addition, the anti-ulcer compositions prepared in
accordance with the present invention may also include materials
such as colorants, anti-oxidants, preservatives, and the like.
Depending upon the carrier material selected for inclusion in the
matrix, the melt-spun medicament product will be in the form of
floss, flakes, spicules and the like. In any event, the scope of
the present invention is not confined to the physical form of the
product, so long as the medicament is sufficiently dispersed
throughout.
In an alternative embodiment, antacid can also be included.
Antacids are any alkaline substance which can be taken internally
to neutralize stomach acidity. Substances which can be used as
antacid include aluminum hydroxide, calcium carbonate, magnesia and
alumina oral suspensions, magnesium oxide, magnesium trisilicate,
magaldrate, simethicone, and sodium bicarbonate. Other substances
can be used and the scope of the invention is not limited to those
substances set forth above.
The embodiment which includes antacids can be prepared with the
antacid combined in the feedstock with the anti-ulcer medicament
and/or analgesic before flash-flow processing. However, in yet
another alterative, antacid can be flash-flow processed separately
and then combined in a delivery system such as a tablet, capsule,
powder, etc. For example, when the flash-flow product is a flake,
separate anti-ulcer flakes and antacid flakes can be mixed and then
tabletted. The resulting tablet carries both actives intimately
bound together in a delivery system, yet physically separated to
reduce chemical interaction. The practitioner will realize yet
other methods for providing the antacid with the anti-ulcer
medicament and, optionally, analgesic compounds using the
flash-flow process, and it is intended to include these other
methods which are within the scope of the present invention.
If desired, the resultant medicament-containing spun matrix can be
compacted to less than 15% of the as-spun volume. An example of
such compacting methods is set forth in commonly- assigned U.S.
Pat. No. 4,997,856, the disclosure of which is incorporated herein.
In addition, the spun matrix may also be reduced in particle size
such as by milling to provide medicament containing either
"particles" or "particulate".
A further aspect of the present invention is a method of treating
ulcer-bearing tissue. The method includes contacting ulcer-bearing
tissue with an anti-ulcer medicament dispersed in a soluble matrix
formed by melt-spinning the medicament with a mixture of a carrier
material and a hydrogel, such as that set forth above as the
anti-ulcer composition.
The medicament containing matrix may be placed in contact with the
ulcer-bearing tissue in the as-spun form, as a compacted wafer or
after being dispersed in a liquid. In the situations where the
matrix is affixed directly to ulcer-bearing tissue, the presence of
the hydrogel in the matrix allows the medicament to be affixed at
the site of treatment. Alternatively, an effective amount of
anti-ulcer composition can be dispersed water and, after
dissolving, can be taken orally for treatment of mouth or other
gastrointestinal mucous-bearing tissue ulcers. The dosages can be
varied depending upon the requirements of the patient and the
severity of the condition being treated. The actual optimum dosage
is within the skill of the artisan.
The compositions of the present invention may also be used as
antacid substitutes for palliative relief of dyspepsia, reflux,
gastritis and the like. In short, it is anticipated that the
medicament-containing spun matrix can be used for any therapeutic
indication for which the medicament included in the matrix is
suited. Moreover, when the compositions of the present invention
include NSAI agents, the unique combination is also preventative in
nature.
EXAMPLES
The following examples serve to provide further appreciation of the
invention but are not meant in any way to restrict the effective
scope of the invention. Unless indicated otherwise, the Econofloss
machine referred to above was used to form the flash-flow
product.
______________________________________ EXAMPLE 1 ANTI-ULCER
COMPOSITION INGREDIENTS WT. (GRAMS)
______________________________________ Sucralfate (Powder) 25.0
Xanthan Gum 2.0 Corn Oil 12.5 Peppermint Oil 0.5 Maltodextrin 35R
(Corn Syrup Solid) 209.5 ______________________________________
In this example, a sucralfate-containing anti-ulcer composition was
prepared. Initially, the carrier material was prepared by mixing
the xanthan gum and maltodextrin until a substantially homogeneous
mixture was obtained. Thereafter, the sucralfate, corn oil and
peppermint oil flavorant were added while mixing was continued. The
resultant mixture was then spun at a low setting. A white
spicule-like flake was obtained.
A one tablespoon quantity of the resulting matrix was added to a
glass of tap water at room temperature. After quickly dissolving, a
colloidal suspension was formed which had a viscosity thicker than
tap water.
The resultant mixture was ingested by a host having distress from
an ulcerated stomach. The inventive composition provided dramatic
relief of stomach ulcer pain instantaneously. It appears that the
unique combination of ingredients subjected to the high shear and
heat processing had a remarkable effect on the speed and the extent
of the treatment.
In the case of treatment of mouth ulcers, one tablespoon of the
resulting matrix is added to two tablespoons of tap water to obtain
a viscous solution which has excellent coating properties. The
viscous solution provides excellent immediate and sustained relief
when used for oral cavity ulcers.
______________________________________ EXAMPLE 2 ANTI-ULCER
COMPOSITION INGREDIENTS WT. (GRAMS)
______________________________________ Sucralfate (Powder) 25.0
Xanthan Gum 1.68 Glycerin 11.25 Maltodextrin 35R (Corn Syrup Solid)
212.07 ______________________________________
In this example, a sucralfate-containing anti-ulcer composition was
prepared. Initially, the carrier material was prepared by mixing
the xanthan gum, sucralfate and glycerin until a substantially
homogeneous mixture was obtained. Thereafter, the Maltodextrin was
added while mixing was continued. The resulting mixture was then
spun at a low setting. A white spicule-like flake was obtained.
Three tablespoons of the spun matrix was mixed with six tablespoons
of water to make a viscous liquid mixture. The viscous mixture was
used as a mouth rinse by a host having severe mouth ulcerations.
About one day after using the viscous rinse, the host observed
substantially reduced irritaiton of the ulcerated areas, especially
when eating food.
______________________________________ EXAMPLE 3 ANTI-ULCER
COMPOSITION INGREDIENTS WT. (GRAMS)
______________________________________ Cimetidine (Powder) 5.0
Xanthan Gum 2.0 Corn Oil 12.5 Peppermint Oil 0.5 Maltodextrin 35R
(Corn Syrup Solid) 209.5 ______________________________________
In this example, the process set forth in Example 1 is repeated
except that the anti-ulcer agent cimetidine is used. A tablespoon
quantity of the resultant spun matrix is added to a glass of water
and quickly dissolves forming a somewhat viscous colloidal
suspension.
The suspension is ingested by a host suffering gastric distress.
The medication quickly relieves the stomach pain associated with
gastritis and dyspepsia. The viscous suspension is also effective
in relieving the discomfort associated with gastrointestinal
reflux, since the viscous liquid adheres to the upper portion of
the gastric mucosa as well as stomach contents.
______________________________________ EXAMPLE 4 ANTI-ULCER
COMPOSITION INGREDIENTS WT. (GRAMS)
______________________________________ Sucralfate (Powder) 25
Xanthan Gum 2 Olive Oil 12.5 Spearmint Oil 0.5 Maltodextrin 35R
(Corn Syrup Solid) 209.5 ______________________________________
In this example, the medicament-containing matrix is prepared as in
the Example 1, except that after the matrix is formed, it is
compacted to about 15% of its as-spun volume in the form of
wafers.
The wafers were then placed on ulcer-bearing oral cavity tissue of
an affected host without being dissolved in water. Once placed on
the ulcer-bearing tissue, the saccharide portion of the matrix
quickly dissolves and the hydrogel portion of the composition,
xanthan gum, along with the medicament remain affixed to the oral
cavity ulcer-bearing tissue to provide instantaneous relief from
the discomfort associated with the ulcerated tissue in the oral
cavity.
Example 5
In this example, the anti-ulcer medicament sucralfate was mixed
with the NSAI agent acetylsalicylic acid. Glycerin was used as a
processing aid and the active ingredients mixed by mortar and
pestle. Corn syrup solids (D.E.=36.5), Maltrin-365, was added and
mixed well. Xanthan gum was also added to form the feedstock. The
ingredients were mixed in the amounts set forth in the Table
below.
______________________________________ 7/26 NSAI PLUS
SUCRALFATE/HYDROGEL Active CSS DE = 36.5 Aid Hydrogel wt % wt % wt
% wt % ______________________________________ Sucralfate 10%
Maltrin-365 74% Glycerin 5% Xanthan Gum1% Acetylsalicylic acid 10%
______________________________________
The feedstock was processed by subjecting the feedstock to
flash-flow conditions in a Tornado spinning machine which had been
modified to control two parameters: temperature of the heating
element, and speed (RPM) of the rotating head. The diameter of the
head was 5.5 inches. The feedstock was processed at 3600 RPM and at
135.degree. C.
The resulting product was in the form of flakes which contained a
substantially uniform dispersion of the active ingredients.
Furthermore, the product had a consistent color and texture, which
made it easily adaptable for inclusion in a delivery system such as
a tablet.
The above example can also be prepared with ibuprofen as a NSAI
agent. The results are a flake which can be easily used in the
formation of a delivery means such as a tabletted pill or
capsule.
Examples 6 & 7
Corn Syrup Solids (D.E.=36.5) were melt spun in combination with
three drugs to produce a flake-like matrix useful in the present
invention. Two examples of this composition feature the drug
sucralfate as the common active ingredient. In addition to
sucralfate, in Example 6 aspirin has been incorporated; and in
Example 7, ibuprofen has been incorporated.
Each composition was formed by first mixing the drugs with a
processing aid (glycerin) by mortar and pestle. The excipient, corn
syrup solid (Maltrin-365), was slowly added and mixed well. The
entire admixture was then processed in a Cuisinart until
homogeneous.
Both example mixtures were melt-spun with a modified Tornado
spinning machine to allow for control of two parameters:
temperature of the heating ribbon, and speed (RPM) of the rotating
head. The diameter of the head was 5.5 inches.
The Table below indicates the relative weight percents of the
melt-spun components as well as the temperature and rotational
speed of the spinning head.
______________________________________ NSAI PLUS SUCRALFATE Example
Drug CSS DE = 36.5 Aid TempC wt % wt % wt % RPM
______________________________________ 6 Sucralfate 10% Maltrin-365
75% Glycerin 5% 3,600 135 Aspirin 10% 7 Sucralfate 10% Maltrin-365
75% Glycerin 5% 3,600 135 Ibuprofen 10%
______________________________________
Flakes were analyzed for the presence of drugs with a Mattson
Galaxy 5020 FTIR against a nitrogen purge background. Samples were
compared to the FTIR spectra of the individual ingredients.
2 grams of each flake example were ground in a SPEX Wig L Bug ball
mill. 5 mg resulting powder was added to 400 mg crystalline KBr and
ground again in SPEX mill. This material was split in two equal
portions to provide duplicate samples for analysis. Pellets were
formed in a SPECAC press by exerting 10 tons of pressure for 1
minute.
IR spectrographs of the melt-spun material confirm the presence of
sucralfate in both examples. Spectrographs also confirm that
Aspirin was present in the processed sample of Example 6, while
Ibuprofen was present in the processed sample of Example 7.
Thus, the product resulting from both example 6 and 7 provide both
preventative and therapeutic effect at the site of delivery.
Example 8
This example demonstrates the use of HPMC as a thickener in
compositions of the present invention. The following composition
was formulated:
______________________________________ INGREDIENTS WEIGHT %
______________________________________ Sulcralfate 11 Maltrin
365.sup.1 68.5 HPMC.sup.2 5.2 Sorbitol 15 Arlacel.sup.3 0.27
______________________________________ .sup.1 maltodextrin (corn
syrup solids) having a dextrose equivalent of 36.5 .sup.2
hydroxypropylmethyl cellulose .sup.3 trademark for a product
containing glycerol monooleate(89%) and propylene glycol(11%)
The Arlacel and HPMC were premixed separately to produce a uniform
blend. The sulcrafate, sorbitol and maltodextrin are also
separately mixed and the HPMC/Arlacel premix is then added to the
sucralfate premix and the two premixes are blended together.
Although these ingredients can be mixed simultaneously with the
other ingredients, premixing is preferred. The mixture was then
divided into two portions. One portion was left as a simple
mixture. The other portion was subjected to the flash flow
processing of the present invention to form the solid matrix. The
mixture was flash flow processed in a 9" cable heater head with a
slit width of 0.025" and processed at temperatures ranging from
122.degree.-132.degree. C. and at speeds of 2160-2640 rpm's. The
resultant product is a fine, dry flake. These flakes constitute the
inventive solid matrix which has been formed from the solid
premixed composition.
Example 9
This example is intended to demonstrate the wettability and
dispersion characteristics of the present invention as compared to
simple admixtures of the identical formulations which have not been
subjected to the flash flow melt spun process. Two portions, each
weighing 36.6 grams a piece of the processed, i.e melt spun,
matrices of Example 8 were placed in separate containers and
reconstituted with 120 ml of water. One of the containers was
shaken 20 times, while the other container was not. The resultant
dispersions and wettability charateristics were observed. In the
container which was shaken, a fine uniform dispersion resulted. All
of the matrix composition was suspended uniformly, demonstrating
substantial wettability of the solid flakes. The container which
was not shaken showed similiar results. In each instance, the solid
matrix rapidly dispersioned upon contact with water.
Photographs of the two above-mentioned dispersions can be observed
in FIGS. 1 and 2. These containers are labelled in the photographs
"Processed-Shaken" and "Processed-Unshaken". It is clear from the
photographs that dispersions made from the inventive process have
enhanced uniformity and wettability as compared to the unprocessed
compositions, i.e. those which were not subjected to the flash flow
melt spun process, as clearly depicted in FIGS. 1 and 2 and marked
accordingly on the containers.
As seen in FIGS. 1 and 2, the containers marked
"Unprocessed-Shaken" and "Unprocessed-Unshaken" did not demonstrate
complete dispersion or wettability, as evidenced by the caking of
the solid mixture on the glass wall of the container. While some
dispersion of the material resulted from those solid particles
which were appropriately wetted, complete dispersability did not
result. This is largely due to the fact that a simple mixture of
the components, even when shaken, does not result in complete
dissolution of the carrier and subsequent suspension of the
particles. The ability of the carrier to rapidly release and
uniformly disperse the medicament is critical for many therapies.
Additionally, in compositions designed for anti-ulcer treatment,
distribution of non-systematic acting medicaments such as
sucralfate must be both uniform, complete and effective in adhering
to mucosal tissue. As evidenced by the simple shake test, the
inventive matrices resulting from flash flow formed compositions,
have significantly enhanced dispersion properties which would be
expected to be similiarly evidenced in the stomach. As a result of
the uniformity in dispersion and excellent wettability of the
inventive matrices, the distribution of the medicament is also
uniform and provides enhanced bioavailability to the situs of
treatment. Thus, the inventive compositions would be expected to
disperse more evenly and completely when ingested and with greater
speed and efficiency such that adherence to mucosal tissue would
likewise be enhanced.
Example 10
This example is intended to demonstrate that conventional mixtures
of identical ingredients as those used to make the inventive
matrices do not result in acceptable dispersions when compared to
those made from the inventive compositions. More specifically, two
unprocessed samples of the composition of Example 8, each weighing
36.6 gm were added in separate containers to 120 ml of water. One
container was shaken 20 times and the resultant dispersion was
observed. The other container was not shaken but water was simply
added to reconstitute the dry ingredients. The resulting
dispersions are depicted in FIGS. 1 and 2 and are marked
"Unprocessed-Shaken" and "Unprocessed-Unshaken". FIGS. 1 and 2 show
that the dispersions were incomplete at best, with much of the dry
powder caking to the bottom of the bottle and failing to wet or go
into appreciable suspension. This effect was even more pronounced
in the sample which was unshaken.
Example 11
This example demonstrates the use of xanthan gum in the inventive
compositions. The following composition was formulated:
______________________________________ INGREDIENTS WEIGHT PERCENT
______________________________________ sucralfate 11.00 Maltrin 365
73.25 sorbitol 15.00 xanthan gum 0.75
______________________________________
A mixture of sucralfate, sorbitol and maltodextrin was blended in a
mixer. Xanthan gum was added to this mixture and further blended
until uniformity was achieved. A sample of this mixture was then
melt spun in accordance with the teachings of this invention. Melt
spinning was performed on a 9" cable heater head with a slit width
of 0.025 inches and at a temperature range of 122.degree. to
126.degree. C. A small, fine white flake resulted. This matrix
product was labelled "Processed." A second sample of the orginally
prepared mixture was also separated out but not processed using
flash flow processing techniques. This mixture was labelled
"Unprocessed."
Two samples of the processed melt spun composition, each weighing
36.6 gm were added to separated containers and reconstituted with
120 ml of water. One container was shaken and the other was allowed
to remain still. The resultant dispersions were then observed. As
seen in FIGS. 3 and 4, the inventive melt spun compositions
exhibited excellent wettability and dispersion properties in both
the shaken and unshaken containers.
Separate samples of the simple, unprocessed mixture prepared above,
each weighing 36.6 gm were reconstituted with 120 ml of water. The
separate containers are exhibited in FIGS. 3 and 4 and are labelled
"Unprocessed-Shaken" and "Unprocessed-Unshaken." As evidenced in
FIGS. 3 and 4, the simple mixtures of the identical ingredients
used in the inventive matrices, did not exhibit wettability
sufficient to make a uniform or complete dispersion. This is
apparent from the caking of the solid powder at the bottom of the
containers. This is readily evident in both the shaken and unshaken
modes, as seen in the photographs.
It is clear from the above examples that dispersions made from the
inventive matrices have better dissolution properties, dispersion
properties and wettability characteristics as compared to the same
ingredients prepared in simple and conventional mixing procedures.
This difference is attributed to the nature and properties of
matrices formed from the inventive melt spin process and which
allow for enhanced rapid and uniform delivery of medicaments.
The dispersions made in Examples 8 through 11, all exhibited
significant stability over several weeks at ambient temperatures.
By stability is meant, the suspension of the medicament in the
aqueous solutions remained stable without settling out to any
significant degree and which can be easily resuspended by moderate
shaking, if necessary.
While there have been described what are presently believed to be
the preferred embodiments of the invention, those skilled in the
art will realize the changes and modifications may be made thereto
without departing from the spirit of the invention, and it is
intended to claim all such changes and modifications as fall within
the true scope of the invention.
* * * * *